HIV and AIDS
More surprises in the development of an HIV vaccine Jose Esparza and Marc H V Van_Regenmortel
Journal Name:
Frontiers in Immunology
ISSN:
1664-3224
Article type:
General Commentary Article
Received on:
23 Jun 2014
Accepted on:
29 Jun 2014
Provisional PDF published on:
29 Jun 2014
www.frontiersin.org:
www.frontiersin.org
Citation:
Esparza J and Van_regenmortel MH(2014) More surprises in the development of an HIV vaccine. Front. Immunol. 5:329. doi:10.3389/fimmu.2014.00329
Copyright statement:
© 2014 Esparza and Van_regenmortel. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
This Provisional PDF corresponds to the article as it appeared upon acceptance, after rigorous peer-review. Fully formatted PDF and full text (HTML) versions will be made available soon.
More surprises in the development of an HIV vaccine José Esparza * and Marc HV Van Regenmortel** * Adjunct Professor, Institute of Human Virology, University of Maryland School of Medicine, Baltimore MD, USA ([email protected]) ** CNRS, UMR7242–Institut de Recherche de l’Ecole de Biotechnologie de Strasbourg (IREBS), Université de Strasbourg, Illkirch 67400, France ([email protected])
In the current issue of Frontiers in Immunology, Jean-Marie Andrieu and collaborators, report results from non-human primate experiments designed to explore a new vaccine concept aimed at inducing tolerance to the simian immunodeficiency virus (SIV) (1). This approach, which is significantly different from other vaccine concepts tested to date, resulted in a surprisingly high level of protection. If the results are confirmed and extended to the human immunodeficiency virus (HIV), this approach may represent a game changing strategy which should be welcomed by a field that has been marred by mostly disappointing results. When HIV was discovered and established as the cause of the Acquired Immune Deficiency Syndrome (AIDS) in 1983-1984, there was an expectation that a preventive vaccine would be rapidly developed (2). Vaccines against several major human viral diseases (polio, measles, mumps, rubella, etc.) were successfully developed during the preceding two or three decades, mostly using live-attenuated viruses, and designed to induce the same type of protective immune responses that develop after natural infection. Moreover, recent advances in molecular biology and recombinant DNA technologies were offering exciting new opportunities for vaccine development, first achieved with the licensure in 1986 of a recombinant vaccine against hepatitis B (3.4). Since the use of whole-inactivated or of live-attenuated vaccines was considered too risky for a pathogen such as HIV, the molecular approach was the one selected by early HIV vaccine developers. That decision was also based on the confidencethat new knowledge on the structure and function of the virus, as well as of the pathogenesis of the disease, will provide the information needed for the rational development of a much needed HIV vaccine (5). In that environment of optimism, the first phase I clinical trials of HIV vaccines started in the United States in 1988. Since then, more than 200 clinical trials have been conducted globally, the majority of them phase I and II trials, to assess the safety and immunogenicity of different vaccine candidates. Those candidate vaccines were developed and tested according to prevailing paradigms that sequentially explored the role of neutralizing antibodies, cell-mediated immunity (CMI) and, more recently, other potential mechanisms of immune protection (2, 6). Although much has been learned from those small-scale clinical trials, the results from phase IIb/III efficacy trials are the ones that have driven major changes on how HIV vaccine research is advanced. Those trials have also given us a few surprises. Fortunately, the field has been able to learn from those lessons and steadily move forward. Perhaps the first major surprise was when in 1994 we learned that field isolates of HIV were more difficult to neutralize in vitro than laboratory-adapted strains, and that proposed existing
candidate vaccines could not induce the appropriate type of neutralizing antibodies, a problem that we are still struggling to solve. Nevertheless, in the early 2000s, two gp120 candidate vaccines from VaxGenwere tested in efficacy trials and, as many predicted, they failed to protect. That failure shifted the field to CMI vaccines and to the suggestion that perhaps the best that an HIV vaccine could do is to decrease virus load in vaccinated individuals who became infected (7). Unfortunately, the STEP study, which tested the CMI concept using an adenovirus 5 vector, and which was a favorite approach of the HIV vaccine community, was halted in 2007 because of lack of efficacy (8). That was a major surprise that led to calls to slow down clinical trials and to go back to basic science (9). The next major surprise came in 2009, when the results from the Thai RV144 were announced. The trial, which evaluated a canarypox prime followed by a gp120 boost, was strongly opposed by some of the leading HIV vaccine scientists (10). Unexpectedly, the trial showed for the first time that prevention of HIV infection was achievable by an HIV vaccine (11). In a commentary authored by the late Norman Letvin (12), who himself expressed concerns about the conduct of the RV144 trial, he indicated that the findings were not expected based on preclinical studies and human immunogenicity data, concluding with the lapidary remark that “we have learned to expect the unexpected in our efforts to generate an effective HIV vaccine.” Although the observed protection in RV144 was modest (31.2%), those results not only brought new optimism to the field, but also triggered a major collaborative effort to try to identify immune correlates of protection (13). In this regard, novel and more promising vaccines are being developed that may result in higher levels of protective efficacy, including the use of vectors based on adenovirus 26 (Ad26) and cytomegalovirus (CMV) (14, 15). Another surprise came when a careful statistical analysis of the Step study confirmed that vaccination in fact enhanced HIV acquisition among a subset of the volunteers (16), an observation that was also been made in the Phambili study conducted in South Africa using the same vaccine as in the Step Study(17). The most likely explanation of the observed enhancement is a specific immune activation induced by the adenovirus 5 vectored vaccines. Although the mechanism is poorly understood, it does not seem to be present with another adenovirus 5 vectored HIV vaccine (18), and it is not clear how relevant itcould be to other vaccine approaches (19). Nevertheless, it is well- known that activation of CD4+ cells is important for HIV replication, which creating a dilemma for vaccinologists, who have to thread a compromise between the desire to induce strong vaccine responses and, at the same time, avoid the immune activation that may enhanced HIV acquisition.In this and other regards, HIV/AIDS is different from other viral diseases for which vaccines have been developed, because forces vaccine developers to explore mechanisms that nature has not developed, especially when dealing with chronic infections (20). It is in this context that Jean Marie Andrieu and collaborators report in this journal (1) additional results from an approach that they first reported in 2012 (21,22). The investigators used Chinese macaques to explore the concept that the induction of immune tolerance to SIV induces protective immunity in the absence of usual humoral or cellular immune responses. To achieve that goal inactivated SIV was intragastrically administered together with living bacterial adjuvants (BCG, Lactobacillus plantrum or Lactobacillus rhamnosus) with the goal of inducing tolerance to the SIV antigens. In a series of experiments, the investigators showed that their approach protected the experimental animals from mucosal
and parenteral challenges. Vaccination did not elicit SIV-specific antibodies nor cytotoxic Tlymphocytes but induced a previously unrecognized population of non-cytolyticMHCIb/Erestricted CD8+T regulatory cells that suppressed the activation of SIV positive CD4+ Tlymphocytes. Although the number of monkeys is relatively small, the levels of protection are impressive, with 23 out of 24 animals protected in one of the experiments, when animals were challenged 48 months after vaccination. The 2012 publication from this group (21) had very little impact in the field, perhaps because it was received with a degree of skepticism. After all, 30 years of intense vaccine research had not resulted in a practical effective vaccine, although an HIV vaccine is sorely needed to bring the HIV epidemic under control. No stone should remain unturned in its search, and the approachreported in this journal should not be dismissed a priori. Instead, it should be carefully considered by other scientists and appropriately confirmed or refuted by additional research. In order to accelerate the development of an HIV vaccine, one of us has proposed a number of actions, including the suggestion to establish a program of truly innovative research with protected funding to explore out-of-the-paradigm approaches, perhaps allocating to this program not less than 10 percent of the total HIV vaccine investment (23). Out-of-the-paradigm approaches, such as the one proposed by Andrieu et al, should be further explored(24). Paraphrasing Dean K Simonton (25),the University of California psychologist who has dedicated his professional life to the study of creativity: Good science contributes ideas that are original and useful, and we have plenty of those in the HIV vaccine field. However, the solution to theHIV vaccine challenge will require genius which, according to Simonton, is characterized not only by originality and usefulness, but also by surprising results.
1.
Andrieu JM, Chen S, Lai C, Guo W, Lu W. Mucosal SIV vaccines comprising inactivated virus particles and bacterial adjuvants induce CD8+T-regulatory cells that suppress SIV positive CD4+cell activation and prevent SIV infection in the macaque model. Frontiers in Immunology (2014)
2.
Esparza J. A brief history of the global effort to develop an HIV vaccine. Vaccine (2013) 31:3502-18.
3.
Valenzuela P, Medina A, Rutter WJ, Ammerer G, Hall BD. Synthesis and assembly of hepatitis B vitus surface antigen particles in yeast. Nature (1982) 298:347-50.
4.
AcAleer WJ, Bynak EB, Maigeter RZ, Wampler DE, Miller WJ, Hilleman MR. Human hepatitis B vaccine from recombinant yeast. Nature (1984) 307:178-80.
5.
Hilleman MR.A simplified vaccinologists’ vaccinology and the pursuit of a vaccine against AIDS. Vaccine (1998) 16:778-93.
6.
Excler JL, Ake J, Robb ML, Kim JH, Plotkin SA. Nonneutralizing functional antibodies: a new “old” paradigm for HIV vaccines. Clin Vaccine Imunol (2014) (in press, June 11; 00230-14).
7.
Johnston MI, Fauci AS. An HIV vaccine– evolving concepts. N Engl J Med (2007) 356:2073-81.
8.
Buchbinder SP, Mehrotra DV, Duerr A, Fitzgerald DW, Mogg R, Li D, et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomized, placebo-controlled, test-of-concept trial. Lancet (2008) 372:1881-93.
9.
Kaiser J. Review of vaccine failure prompts to basic science. Science (2008) 320:301.
10.
Burton DR, Desrosiers RC, Doms RW, Feinberg MB, Gallo RC, Hahn B, et al. A sound rationale needed for phase III HIV-1 vaccine trials. Science (2004) 3036):316.
11.
Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med (2009) 361:2209-20.
12.
Letvin NL. Moving forward in HIV vaccine development. Science (2009) 326:11968.
13.
Haynes BF, Gilbert PB, McElrath MJ, Zolla-Pazner S, Tomaras G, Alam S et al. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N Engl J Med (2012) 366:1275-86.
14.
Baden LR, Walsh SR, Seaman MS, Tucker RP, Krause KH,Patel A, et al. First-inhuman evaluation of the safety and immunogenicity of a recombinant adenovirus serotype 26 HIV-1 Env vaccine (IPCAVD 001). J Infect Dis (2013) 207:240-7.
15.
Hansen SG, Sacha JB, Hughes CM, Ford JC, Burwitz BJ, Scholz I, et al.Cytomegalovirus vectors violate CD8+ T cell epitope recognition paradigms. Science (2013) 340.
16.
Duerr A, Huang Y, Buchbinder S, Coombs RW, Sanchez J, del Rio C et al. Extended follow-up confirms early vaccine-enhanced risk of HIV acquisition and demonstrates waning effect over time among participants in a randomized trial of recombinant adenovirus HIV vaccine (Step Study). J Infect Dis (2012) 206:258-66.
17.
Gray GE, Moodie Z, Metch B, Gilbert PB, Bekker L-G, Churchyard G et al. Recombinant adenovirus type 5 HIV gag/pol/nef vaccine in South Africa: unblinded, long-term follow-up of the phase 2b HVTN503/Phambili study. Lancet Infect Dis (2014) 14:388-96.
18.
Hammer SM, Sobieszczyk ME, Janes H, Karuna ST, Mulligan MJ, Groves D et al. Efficacy trial of a DNA/rAds HIV-1 preventive vaccine. N Engl J Med (2013) 369:2083-92.
19.
Fauci AS, Marovich MA, Dieffenbach CW, Hunter E, BuchbinderSP. Immune activation with HIV vaccines. Science (2014) 344:49-51.
20.
Johnston MI, Fauci AS. HIV vaccine development-improving on natural immunity. N Engl J Med (2011) 365:873-5.
21.
Lu W, Chen S, Lai C, Guo W, Andrieu J-M. Induction of CD8+ regulatory T cells protects macaques against SIV challenge. Cell Rep (2012) 2:1736-46.
22.
Van Regenmortel MHV. An oral tolerogenic vaccine protects macaques from SIV infection without eliciting SIV-specific antibodies nor CTLs. J AIDS Clin Res (2013) 4:2.
23.
Esparza J. What has 30 years of HIV vaccine research taught us? Vaccines (2013) 1:513-26.
24.
Van Regenmortel MHV, Andrieu J-M, Dimitrov DS, Ensoli B, Hioe CE, Moog C, Ruprecht RM. Paradigm changes and the future of HIV vaccines: A summary of a workshop held in Baltimore on 20 November 2013. J AIDS Clin Res (2014) 5:281. doi: 10.4172/2155-6113.1000281.
25.
Simonton DK. After Einstein: Scientific genius is extinct. Nature (2013) 493:602.
Copyright of Frontiers in Immunology is the property of Frontiers Media S.A. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
More surprises in the development of an HIV vaccine Jose Esparza and Marc H V Van_Regenmortel
Journal Name:
Frontiers in Immunology
ISSN:
1664-3224
Article type:
General Commentary Article
Received on:
23 Jun 2014
Accepted on:
29 Jun 2014
Provisional PDF published on:
29 Jun 2014
www.frontiersin.org:
www.frontiersin.org
Citation:
Esparza J and Van_regenmortel MH(2014) More surprises in the development of an HIV vaccine. Front. Immunol. 5:329. doi:10.3389/fimmu.2014.00329
Copyright statement:
© 2014 Esparza and Van_regenmortel. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
This Provisional PDF corresponds to the article as it appeared upon acceptance, after rigorous peer-review. Fully formatted PDF and full text (HTML) versions will be made available soon.
More surprises in the development of an HIV vaccine José Esparza * and Marc HV Van Regenmortel** * Adjunct Professor, Institute of Human Virology, University of Maryland School of Medicine, Baltimore MD, USA ([email protected]) ** CNRS, UMR7242–Institut de Recherche de l’Ecole de Biotechnologie de Strasbourg (IREBS), Université de Strasbourg, Illkirch 67400, France ([email protected])
In the current issue of Frontiers in Immunology, Jean-Marie Andrieu and collaborators, report results from non-human primate experiments designed to explore a new vaccine concept aimed at inducing tolerance to the simian immunodeficiency virus (SIV) (1). This approach, which is significantly different from other vaccine concepts tested to date, resulted in a surprisingly high level of protection. If the results are confirmed and extended to the human immunodeficiency virus (HIV), this approach may represent a game changing strategy which should be welcomed by a field that has been marred by mostly disappointing results. When HIV was discovered and established as the cause of the Acquired Immune Deficiency Syndrome (AIDS) in 1983-1984, there was an expectation that a preventive vaccine would be rapidly developed (2). Vaccines against several major human viral diseases (polio, measles, mumps, rubella, etc.) were successfully developed during the preceding two or three decades, mostly using live-attenuated viruses, and designed to induce the same type of protective immune responses that develop after natural infection. Moreover, recent advances in molecular biology and recombinant DNA technologies were offering exciting new opportunities for vaccine development, first achieved with the licensure in 1986 of a recombinant vaccine against hepatitis B (3.4). Since the use of whole-inactivated or of live-attenuated vaccines was considered too risky for a pathogen such as HIV, the molecular approach was the one selected by early HIV vaccine developers. That decision was also based on the confidencethat new knowledge on the structure and function of the virus, as well as of the pathogenesis of the disease, will provide the information needed for the rational development of a much needed HIV vaccine (5). In that environment of optimism, the first phase I clinical trials of HIV vaccines started in the United States in 1988. Since then, more than 200 clinical trials have been conducted globally, the majority of them phase I and II trials, to assess the safety and immunogenicity of different vaccine candidates. Those candidate vaccines were developed and tested according to prevailing paradigms that sequentially explored the role of neutralizing antibodies, cell-mediated immunity (CMI) and, more recently, other potential mechanisms of immune protection (2, 6). Although much has been learned from those small-scale clinical trials, the results from phase IIb/III efficacy trials are the ones that have driven major changes on how HIV vaccine research is advanced. Those trials have also given us a few surprises. Fortunately, the field has been able to learn from those lessons and steadily move forward. Perhaps the first major surprise was when in 1994 we learned that field isolates of HIV were more difficult to neutralize in vitro than laboratory-adapted strains, and that proposed existing
candidate vaccines could not induce the appropriate type of neutralizing antibodies, a problem that we are still struggling to solve. Nevertheless, in the early 2000s, two gp120 candidate vaccines from VaxGenwere tested in efficacy trials and, as many predicted, they failed to protect. That failure shifted the field to CMI vaccines and to the suggestion that perhaps the best that an HIV vaccine could do is to decrease virus load in vaccinated individuals who became infected (7). Unfortunately, the STEP study, which tested the CMI concept using an adenovirus 5 vector, and which was a favorite approach of the HIV vaccine community, was halted in 2007 because of lack of efficacy (8). That was a major surprise that led to calls to slow down clinical trials and to go back to basic science (9). The next major surprise came in 2009, when the results from the Thai RV144 were announced. The trial, which evaluated a canarypox prime followed by a gp120 boost, was strongly opposed by some of the leading HIV vaccine scientists (10). Unexpectedly, the trial showed for the first time that prevention of HIV infection was achievable by an HIV vaccine (11). In a commentary authored by the late Norman Letvin (12), who himself expressed concerns about the conduct of the RV144 trial, he indicated that the findings were not expected based on preclinical studies and human immunogenicity data, concluding with the lapidary remark that “we have learned to expect the unexpected in our efforts to generate an effective HIV vaccine.” Although the observed protection in RV144 was modest (31.2%), those results not only brought new optimism to the field, but also triggered a major collaborative effort to try to identify immune correlates of protection (13). In this regard, novel and more promising vaccines are being developed that may result in higher levels of protective efficacy, including the use of vectors based on adenovirus 26 (Ad26) and cytomegalovirus (CMV) (14, 15). Another surprise came when a careful statistical analysis of the Step study confirmed that vaccination in fact enhanced HIV acquisition among a subset of the volunteers (16), an observation that was also been made in the Phambili study conducted in South Africa using the same vaccine as in the Step Study(17). The most likely explanation of the observed enhancement is a specific immune activation induced by the adenovirus 5 vectored vaccines. Although the mechanism is poorly understood, it does not seem to be present with another adenovirus 5 vectored HIV vaccine (18), and it is not clear how relevant itcould be to other vaccine approaches (19). Nevertheless, it is well- known that activation of CD4+ cells is important for HIV replication, which creating a dilemma for vaccinologists, who have to thread a compromise between the desire to induce strong vaccine responses and, at the same time, avoid the immune activation that may enhanced HIV acquisition.In this and other regards, HIV/AIDS is different from other viral diseases for which vaccines have been developed, because forces vaccine developers to explore mechanisms that nature has not developed, especially when dealing with chronic infections (20). It is in this context that Jean Marie Andrieu and collaborators report in this journal (1) additional results from an approach that they first reported in 2012 (21,22). The investigators used Chinese macaques to explore the concept that the induction of immune tolerance to SIV induces protective immunity in the absence of usual humoral or cellular immune responses. To achieve that goal inactivated SIV was intragastrically administered together with living bacterial adjuvants (BCG, Lactobacillus plantrum or Lactobacillus rhamnosus) with the goal of inducing tolerance to the SIV antigens. In a series of experiments, the investigators showed that their approach protected the experimental animals from mucosal
and parenteral challenges. Vaccination did not elicit SIV-specific antibodies nor cytotoxic Tlymphocytes but induced a previously unrecognized population of non-cytolyticMHCIb/Erestricted CD8+T regulatory cells that suppressed the activation of SIV positive CD4+ Tlymphocytes. Although the number of monkeys is relatively small, the levels of protection are impressive, with 23 out of 24 animals protected in one of the experiments, when animals were challenged 48 months after vaccination. The 2012 publication from this group (21) had very little impact in the field, perhaps because it was received with a degree of skepticism. After all, 30 years of intense vaccine research had not resulted in a practical effective vaccine, although an HIV vaccine is sorely needed to bring the HIV epidemic under control. No stone should remain unturned in its search, and the approachreported in this journal should not be dismissed a priori. Instead, it should be carefully considered by other scientists and appropriately confirmed or refuted by additional research. In order to accelerate the development of an HIV vaccine, one of us has proposed a number of actions, including the suggestion to establish a program of truly innovative research with protected funding to explore out-of-the-paradigm approaches, perhaps allocating to this program not less than 10 percent of the total HIV vaccine investment (23). Out-of-the-paradigm approaches, such as the one proposed by Andrieu et al, should be further explored(24). Paraphrasing Dean K Simonton (25),the University of California psychologist who has dedicated his professional life to the study of creativity: Good science contributes ideas that are original and useful, and we have plenty of those in the HIV vaccine field. However, the solution to theHIV vaccine challenge will require genius which, according to Simonton, is characterized not only by originality and usefulness, but also by surprising results.
1.
Andrieu JM, Chen S, Lai C, Guo W, Lu W. Mucosal SIV vaccines comprising inactivated virus particles and bacterial adjuvants induce CD8+T-regulatory cells that suppress SIV positive CD4+cell activation and prevent SIV infection in the macaque model. Frontiers in Immunology (2014)
2.
Esparza J. A brief history of the global effort to develop an HIV vaccine. Vaccine (2013) 31:3502-18.
3.
Valenzuela P, Medina A, Rutter WJ, Ammerer G, Hall BD. Synthesis and assembly of hepatitis B vitus surface antigen particles in yeast. Nature (1982) 298:347-50.
4.
AcAleer WJ, Bynak EB, Maigeter RZ, Wampler DE, Miller WJ, Hilleman MR. Human hepatitis B vaccine from recombinant yeast. Nature (1984) 307:178-80.
5.
Hilleman MR.A simplified vaccinologists’ vaccinology and the pursuit of a vaccine against AIDS. Vaccine (1998) 16:778-93.
6.
Excler JL, Ake J, Robb ML, Kim JH, Plotkin SA. Nonneutralizing functional antibodies: a new “old” paradigm for HIV vaccines. Clin Vaccine Imunol (2014) (in press, June 11; 00230-14).
7.
Johnston MI, Fauci AS. An HIV vaccine– evolving concepts. N Engl J Med (2007) 356:2073-81.
8.
Buchbinder SP, Mehrotra DV, Duerr A, Fitzgerald DW, Mogg R, Li D, et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomized, placebo-controlled, test-of-concept trial. Lancet (2008) 372:1881-93.
9.
Kaiser J. Review of vaccine failure prompts to basic science. Science (2008) 320:301.
10.
Burton DR, Desrosiers RC, Doms RW, Feinberg MB, Gallo RC, Hahn B, et al. A sound rationale needed for phase III HIV-1 vaccine trials. Science (2004) 3036):316.
11.
Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med (2009) 361:2209-20.
12.
Letvin NL. Moving forward in HIV vaccine development. Science (2009) 326:11968.
13.
Haynes BF, Gilbert PB, McElrath MJ, Zolla-Pazner S, Tomaras G, Alam S et al. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N Engl J Med (2012) 366:1275-86.
14.
Baden LR, Walsh SR, Seaman MS, Tucker RP, Krause KH,Patel A, et al. First-inhuman evaluation of the safety and immunogenicity of a recombinant adenovirus serotype 26 HIV-1 Env vaccine (IPCAVD 001). J Infect Dis (2013) 207:240-7.
15.
Hansen SG, Sacha JB, Hughes CM, Ford JC, Burwitz BJ, Scholz I, et al.Cytomegalovirus vectors violate CD8+ T cell epitope recognition paradigms. Science (2013) 340.
16.
Duerr A, Huang Y, Buchbinder S, Coombs RW, Sanchez J, del Rio C et al. Extended follow-up confirms early vaccine-enhanced risk of HIV acquisition and demonstrates waning effect over time among participants in a randomized trial of recombinant adenovirus HIV vaccine (Step Study). J Infect Dis (2012) 206:258-66.
17.
Gray GE, Moodie Z, Metch B, Gilbert PB, Bekker L-G, Churchyard G et al. Recombinant adenovirus type 5 HIV gag/pol/nef vaccine in South Africa: unblinded, long-term follow-up of the phase 2b HVTN503/Phambili study. Lancet Infect Dis (2014) 14:388-96.
18.
Hammer SM, Sobieszczyk ME, Janes H, Karuna ST, Mulligan MJ, Groves D et al. Efficacy trial of a DNA/rAds HIV-1 preventive vaccine. N Engl J Med (2013) 369:2083-92.
19.
Fauci AS, Marovich MA, Dieffenbach CW, Hunter E, BuchbinderSP. Immune activation with HIV vaccines. Science (2014) 344:49-51.
20.
Johnston MI, Fauci AS. HIV vaccine development-improving on natural immunity. N Engl J Med (2011) 365:873-5.
21.
Lu W, Chen S, Lai C, Guo W, Andrieu J-M. Induction of CD8+ regulatory T cells protects macaques against SIV challenge. Cell Rep (2012) 2:1736-46.
22.
Van Regenmortel MHV. An oral tolerogenic vaccine protects macaques from SIV infection without eliciting SIV-specific antibodies nor CTLs. J AIDS Clin Res (2013) 4:2.
23.
Esparza J. What has 30 years of HIV vaccine research taught us? Vaccines (2013) 1:513-26.
24.
Van Regenmortel MHV, Andrieu J-M, Dimitrov DS, Ensoli B, Hioe CE, Moog C, Ruprecht RM. Paradigm changes and the future of HIV vaccines: A summary of a workshop held in Baltimore on 20 November 2013. J AIDS Clin Res (2014) 5:281. doi: 10.4172/2155-6113.1000281.
25.
Simonton DK. After Einstein: Scientific genius is extinct. Nature (2013) 493:602.
Copyright of Frontiers in Immunology is the property of Frontiers Media S.A. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
